Mepron

"Alderman Farms Sales Corporation, Boynton Beach, Florida is recalling one pint containers of Certified Organic Cherry Tomatoes because they have the potential to be contaminated with Salmonella, an organism which can cause serious and some"...

Mepron

CLINICAL PHARMACOLOGY

Microbiology

Mechanism of Action

Atovaquone is a
hydroxy-1,4-naphthoquinone, an analog of ubiquinone, with antipneumocystis
activity. The mechanism of action against Pneumocystis jiroveci has not
been fully elucidated. In Plasmodium species, the site of action appears
to be the cytochrome bc1 complex (Complex III). Several metabolic enzymes are
linked to the mitochondrial electron transport chain via ubiquinone. Inhibition
of electron transport by atovaquone will result in indirect inhibition of these
enzymes. The ultimate metabolic effects of such blockade may include inhibition
of nucleic acid and ATP synthesis.

Activity In Vitro

Several laboratories, using
different in vitro methodologies, have shown the IC50 (50% inhibitory
concentration) of atovaquone against rat P. jiroveci to be in the range
of 0.1 to 3.0 mcg/mL.

Drug Resistance

Phenotypic resistance to
atovaquone in vitro has not been demonstrated for P. jiroveci. However,
in 2 patients who developed Pneumocystis carinii pneumonia (PCP) after
prophylaxis with atovaquone, DNA sequence analysis identified mutations in the
predicted amino acid sequence of P. jiroveci cytochrome b (a likely
target site for atovaquone). The clinical significance of this is unknown.

Pharmacokinetics

Absorption

Atovaquone is a highly lipophilic compound with low
aqueous solubility. The bioavailability of atovaquone is highly dependent on
formulation and diet. The suspension formulation provides an approximately 2-fold
increase in atovaquone bioavailability in the fasting or fed state compared to
the previously marketed tablet formulation. The absolute bioavailability of a
750-mg dose of MEPRON Suspension administered under fed conditions in 9
HIV-infected (CD4 > 100 cells/mm³) volunteers was 47% ±
15%. In the same study, the bioavailability of a 750-mg dose of the previously
marketed tablet formulation was 23% ± 11%.

Administering atovaquone with food enhances its
absorption by approximately 2 fold. In one study, 16 healthy volunteers
received a single dose of 750 mg MEPRON Suspension after an overnight fast and
following a standard breakfast (23 g fat: 610 kCal). The mean (±SD) area
under the concentration-time curve (AUC) values were 324 ± 115 and 801
± 320 hr•mcg/mL
under fasting and fed conditions, respectively, representing a 2.6 ±
1.0-fold increase. The effect of food (23 g fat: 400 kCal) on plasma atovaquone
concentrations was also evaluated in a multiple-dose, randomized, crossover
study in 19 HIV-infected volunteers (CD4 < 200 cells/mm³)
receiving daily doses of 500 mg MEPRON Suspension. AUC was 280 ± 114 hr•mcg/mL when atovaquone
was administered with food as compared to 169 ± 77 hr•mcg/mL under fasting
conditions. Maximum plasma atovaquone concentration (Cmax) was 15.1 ±
6.1 and 8.8 ± 3.7 mcg/mL when atovaquone was administered with food and
under fasting conditions, respectively.

Distribution

Following the intravenous administration of atovaquone,
the volume of distribution at steady state (Vdss) was 0.60 ± 0.17 L/kg
(n = 9). Atovaquone is extensively bound to plasma proteins (99.9%) over the
concentration range of 1 to 90 mcg/mL. In 3 HIV-infected children who received
750 mg atovaquone as the tablet formulation 4 times daily for 2 weeks, the cerebrospinal
fluid concentrations of atovaquone were 0.04, 0.14, and 0.26 mcg/mL,
representing less than 1% of the plasma concentration.

Elimination

The plasma clearance of atovaquone following intravenous
(IV) administration in 9 HIV-infected volunteers was 10.4 ± 5.5 mL/min
(0.15 ± 0.09 mL/min/kg). The half-life of atovaquone was 62.5 ±
35.3 hours after IV administration and ranged from 67.0 ± 33.4 to 77.6 ±
23.1 hours across studies following administration of MEPRON Suspension. The
half-life of atovaquone is long due to presumed enterohepatic cycling and
eventual fecal elimination. In a study where 14C-labelled atovaquone
was administered to healthy volunteers, greater than 94% of the dose was
recovered as unchanged atovaquone in the feces over 21 days. There was little
or no excretion of atovaquone in the urine (less than 0.6%). There is indirect
evidence that atovaquone may undergo limited metabolism; however, a specific
metabolite has not been identified.

Special Populations

Pediatrics

In a study of MEPRON Suspension in 27 HIV-infected,
asymptomatic infants and children between 1 month and 13 years of age, the
pharmacokinetics of atovaquone were age dependent. These patients were dosed
once daily with food for 12 days. The average steady-state plasma atovaquone
concentrations in the 24 patients with available concentration data are shown
in Table 1.

Hepatic/Renal Impairment

The pharmacokinetics of
atovaquone have not been studied in patients with hepatic or renal impairment.

Drug Interactions

Rifampin

In a study with 13 HIV-infected
volunteers, the oral administration of rifampin 600 mg every 24 hours with
MEPRON Suspension 750 mg every 12 hours resulted in a 52% ± 13% decrease in the average steady-state plasma
atovaquone concentration and a 37% ± 42% increase
in the average steady-state plasma rifampin concentration. The half-life of
atovaquone decreased from 82 ± 36 hours
when administered without rifampin to 50 ± 16 hours with rifampin.

Rifabutin, another rifamycin,
is structurally similar to rifampin and may possibly have some of the same drug
interactions as rifampin. No interaction trials have been conducted with MEPRON
and rifabutin.

Trimethoprim/Sulfamethoxazole (TMP-SMX)

The possible interaction between atovaquone and TMP-SMX
was evaluated in 6 HIV-infected adult volunteers as part of a larger
multiple-dose, dose-escalation, and chronic dosing study of MEPRON Suspension.
In this crossover study, MEPRON Suspension 500 mg once daily, or TMP-SMX
tablets (160 mg trimethoprim and 800 mg sulfamethoxazole) twice daily, or the
combination were administered with food to achieve steady state. No difference
was observed in the average steady-state plasma atovaquone concentration after
coadministration with TMP-SMX. Coadministration of MEPRON with TMP-SMX resulted
in a 17% and 8% decrease in average steady-state concentrations of trimethoprim
and sulfamethoxazole in plasma, respectively. This effect is minor and would
not be expected to produce clinically significant events.

Zidovudine

Data from 14 HIV-infected volunteers who were given
atovaquone tablets 750 mg every 12 hours with zidovudine 200 mg every 8 hours
showed a 24% ± 12% decrease in zidovudine apparent oral clearance,
leading to a 35% ± 23% increase in plasma zidovudine AUC. The
glucuronide metabolite:parent ratio decreased from a mean of 4.5 when
zidovudine was administered alone to 3.1 when zidovudine was administered with
atovaquone tablets. This effect is minor and would not be expected to produce
clinically significant events. Zidovudine had no effect on atovaquone
pharmacokinetics.

In a comparative study of atovaquone tablets with TMP-SMX
for oral treatment of mild-to-moderate PCP (see INDICATIONS AND USAGE),
where AIDS patients received 750 mg atovaquone tablets 3 times daily for 21
days, the mean steady-state atovaquone concentration was 13.9 ± 6.9
mcg/mL (n = 133). Analysis of these data established a relationship between
plasma atovaquone concentration and successful treatment. This is shown in
Table 2.

aSuccessful treatment was defined as improvement in clinical
and respiratory measures persisting at least 4 weeks after cessation of
therapy. This was based on data from patients for which both outcome and
steady-state plasma atovaquone concentration data are available. bBased on logistic regression analysis.

A dosing regimen of MEPRON Suspension for the treatment
of mild-to-moderate PCP has been selected to achieve average plasma atovaquone
concentrations of approximately 20 mcg/mL, because this plasma concentration
was previously shown to be well tolerated and associated with the highest
treatment success rates (Table 2). In an open-label PCP treatment study with
MEPRON Suspension, dosing regimens of 1,000 mg once daily, 750 mg twice daily,
1,500 mg once daily, and 1,000 mg twice daily were explored. The average
steady-state plasma atovaquone concentration achieved at the 750-mg twice-daily
dose given with meals was 22.0 ± 10.1 mcg/mL (n = 18).

Last reviewed on RxList: 3/21/2013
This monograph has been modified to include the generic and brand name in many instances.